Excessive weight, and in extreme cases obesity, is a widespread medical problem. This may be due in part to sedentary life styles and poor diet (high in fats and carbohydrates), as well as to a genetic predisposition in many cases. Obesity is a well-known risk factor for hypertension, Type 2 diabetes and cardiovascular diseases.
Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus. There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone that regulates glucose utilization. In Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance. Both obesity and Type 2 diabetes are characterized by peripheral tissue insulin resistance.
The prevalence of insulin resistance in glucose intolerant subjects has long been recognized. Reaven et al (American Journal of Medicine, 60, 80, 1976) used a continuous infusion of glucose and insulin (insulin/glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance existed in a diverse group of nonobese, nonketotic subjects. These subjects ranged from borderline glucose tolerant to overt, fasting hyperglycemia. The diabetic groups in these studies included both insulin dependent (Type 1) and noninsulin dependent (Type 2) subjects.
Coincident with sustained insulin resistance is the more easily determined hyperinsulinemia, which can be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia can be present as a result of insulin resistance, such as is in obese and/or diabetic (Type 2) subjects and/or glucose intolerant subjects, or in Type 1 subjects, as a consequence of overdose of injected insulin compared with normal physiological release of the hormone by the endocrine pancreas.
The independent risk factors such as obesity and hypertension for atherosclerotic diseases are also associated with insulin resistance. Using a combination of insulin/glucose clamps, tracer glucose infusion and indirect calorimetry, it has been demonstrated that the insulin resistance of essential hypertension is located in peripheral tissues (principally muscle) and correlates directly with the severity of hypertension (Diabetes Care, 14, 173, 1991). In hypertension of the obese, insulin resistance generates hyperinsulinemia, which is recruited as a mechanism to limit further weight gain via thermogenesis, but insulin also increases renal sodium reabsorption and stimulates the sympathetic nervous system in kidneys, heart, and vasculature, creating hypertension.
It is now appreciated that insulin resistance is usually the result of a defect in the insulin receptor signaling system, at a site post binding of insulin to the receptor. Accumulated scientific evidence demonstrating insulin resistance in the major tissues which respond to insulin (muscle, liver, adipose), strongly suggests that a defect in insulin signal transduction resides at an early step in this cascade, specifically at the insulin receptor kinase activity, which appears to be diminished (Diabetalogia, 34, 848, 1991).
In the recent past, a new class of drugs, which act by reducing peripheral insulin resistance has been developed. These drugs are ligands for the nuclear receptor, peroxisome proliferator-activated receptor gamma isoform (PPAR gamma), expressed primarily in the adipose tissue. These drugs act as insulin sensitizers in reducing blood sugar and hyperinsulinemia. The most common side effects of these PPAR gamma activators are weight gain, edema, increased risk of stroke and heart attack.
Diabetic patients are at an increased risk of developing cardiovascular disease events due to risk factors such as dyslipidemia, obesity, hypertension, glucose intolerance. The presence of the above risk factors in an individual is collectively called metabolic syndrome. According to National Cholesterol Expert Panel's ATP III criteria, dyslipidemia is defined as a state in which an individual exhibits a combination of triglyceride levels of 150 mg/dl and above and HDL cholesterol level of less than 40 mg/dl in men and less than 50 mg/dl in women. (J. Am. Med. Association, 285, 2486-2497, 2001).
U.S. Pat. No. 6,583,157 discloses quinolinyl and benzothiazolyl compounds as PPAR modulators. U.S. Pat. No. 6,403,607 discloses sulfonamide derivatives exhibiting effects in the treatment of peptic ulcer and a drug comprising the derivative as an active ingredient.
U.S. Pat. No. 6,262,112 and U.S. Pat. No. 6,573,278 disclose aryl sulfonamides and analogues and their use in the treatment of neurodegenerative diseases.
There is a need for improved and alternative medicaments for the treatment of metabolic disorders related to insulin resistance or hyperglycemia.